There is considerable epidemiologic evidence that alcohol intake is related to risk of breast cancer and that intake of vegetables and fruits may reduce risk. Utilizing an existing case control study, we propose to examine two etiological mechanisms, one-carbon metabolism and/or oxidative stress and breast cancer. Our first aim is to examine the relation of elements related to one-carbon metabolism with risk. We propose a) to investigate genetic variation in enzymes important in one-carbon metabolism (methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MS) and cystathione B-synthase (CBS)) in relation to risk and to investigate interaction of these genetic factors with dietary folate and alcohol with breast cancer risk; b) to investigate the association of dietary folate and alcohol and these genetic factors with total p53 mutations and with particular p53 mutations and c) to investigate the association of dietary folate and alcohol and these genetic factors with hypermethylation of the p16 gene, the BRCA1 gene and the estrogen receptor gene in breast tumors. Our second aim is to examine elements related to oxidative stress and antioxidants with risk. We propose to a) examine the relation of genetic variation in an enzyme important in the control of oxidative balance (manganese superoxide dismutase (MnSOD)) and to examine interactions of this genetic factor with dietary factors both oxidants and antioxidants; and b) to investigate the association between dietary sources of oxidants and antioxidants with total and particular p53 mutations. By combining information on intake, genetic susceptibility and tumor characteristics, it will be possible to make clearer inferences about the role of these two mechanisms in breast cancer etiology, with potentially important public health implications.